Natural history of progression of HPV infection to cervical lesion or clearance: analysis of the control arm of the large, randomised PATRICIA study

Unnop Jaisamrarn, Xavier Castellsagué, Suzanne M Garland, Paulo Naud, Johanna Palmroth, Maria Rowena Del Rosario-Raymundo, Cosette M Wheeler, Jorge Salmerón, Song-Nan Chow, Dan Apter, Julio C Teixeira, S Rachel Skinner, James Hedrick, Anne Szarewski, Barbara Romanowski, Fred Y Aoki, Tino F Schwarz, Willy A J Poppe, F Xavier Bosch, Newton S de Carvalho, Maria Julieta Germar, Klaus Peters, Jorma Paavonen, Marie-Cecile Bozonnat, Dominique Descamps, Frank Struyf, Gary O Dubin, Dominique Rosillon, Laurence Baril, HPV PATRICIA Study Group, I Denham, S M Garland, A Mindel, S R Skinner, P De Sutter, W A J Poppe, W Tjalma, N S De Carvalho, P Naud, J C Teixeira, F Y Aoki, F Diaz-Mitoma, M Dionne, L Ferguson, M Miller, K Papp, B Ramjattan, B Romanowski, P H Orr, R Somani, D Apter, T Karppa, N Kudjoi, L Kyha-Österlund, M Lehtinen, K Lönnberg, T Lunnas, J Paavonen, J Palmroth, T Petaja, M Vilkki, T Gent, T Grubert, W D Höpker, K Peters, K Schulze, T F Schwarz, J Salmerón, C Crisostomo, M R Del Rosario-Raymundo, J E Raymundo, M J Germar, G Limson, C Remollino, G Villanueva, S Villanueva, J D Zamora, J Bajo-Arenas, J Bayas, M Campins, X Castellsagué, M Castro, C Centeno, M L Rodríguez de la Pinta, A Torné, J A Vidart, S N Chow, M H Yu, S Angsuwathana, U Jaisamrarn, M Cruickshank, E A Hakim, H Kitchener, D Lewis, A Szarewski, R Ackerman, M Caldwell, C Chambers, A Chatterjee, L DeMars, L Downs, P Fine, J Hedrick, W Huh, T Klein, J Lalezari, S Luber, M Martens, C Peterson, J Rosen, L Seidman, M Sperling, R Sperling, M Stager, J Stapleton, K Swenson, C Thoming, L Twiggs, A Waldbaum, C M Wheeler, A Camier, B Colau, S Genevrois, P Marius, N Martens, T Ouammou, M Rahier, B Spiessens, A Meurée, N Houard, F Dessy, A Tonglet, A S Vilain, C Van Hoof, H Bhat, E Alt, B Iskaros, A Limaye, R D Luff, M McNeeley, B Winkler, A Molijn, W Quint, L Struijk, M Van de Sandt, L J Van Doorn, N Kiviat, K P Klugman, P Nieminen, C Bergeron, E Eisenstein, R Marks, T Nolan, S K Tay, Unnop Jaisamrarn, Xavier Castellsagué, Suzanne M Garland, Paulo Naud, Johanna Palmroth, Maria Rowena Del Rosario-Raymundo, Cosette M Wheeler, Jorge Salmerón, Song-Nan Chow, Dan Apter, Julio C Teixeira, S Rachel Skinner, James Hedrick, Anne Szarewski, Barbara Romanowski, Fred Y Aoki, Tino F Schwarz, Willy A J Poppe, F Xavier Bosch, Newton S de Carvalho, Maria Julieta Germar, Klaus Peters, Jorma Paavonen, Marie-Cecile Bozonnat, Dominique Descamps, Frank Struyf, Gary O Dubin, Dominique Rosillon, Laurence Baril, HPV PATRICIA Study Group, I Denham, S M Garland, A Mindel, S R Skinner, P De Sutter, W A J Poppe, W Tjalma, N S De Carvalho, P Naud, J C Teixeira, F Y Aoki, F Diaz-Mitoma, M Dionne, L Ferguson, M Miller, K Papp, B Ramjattan, B Romanowski, P H Orr, R Somani, D Apter, T Karppa, N Kudjoi, L Kyha-Österlund, M Lehtinen, K Lönnberg, T Lunnas, J Paavonen, J Palmroth, T Petaja, M Vilkki, T Gent, T Grubert, W D Höpker, K Peters, K Schulze, T F Schwarz, J Salmerón, C Crisostomo, M R Del Rosario-Raymundo, J E Raymundo, M J Germar, G Limson, C Remollino, G Villanueva, S Villanueva, J D Zamora, J Bajo-Arenas, J Bayas, M Campins, X Castellsagué, M Castro, C Centeno, M L Rodríguez de la Pinta, A Torné, J A Vidart, S N Chow, M H Yu, S Angsuwathana, U Jaisamrarn, M Cruickshank, E A Hakim, H Kitchener, D Lewis, A Szarewski, R Ackerman, M Caldwell, C Chambers, A Chatterjee, L DeMars, L Downs, P Fine, J Hedrick, W Huh, T Klein, J Lalezari, S Luber, M Martens, C Peterson, J Rosen, L Seidman, M Sperling, R Sperling, M Stager, J Stapleton, K Swenson, C Thoming, L Twiggs, A Waldbaum, C M Wheeler, A Camier, B Colau, S Genevrois, P Marius, N Martens, T Ouammou, M Rahier, B Spiessens, A Meurée, N Houard, F Dessy, A Tonglet, A S Vilain, C Van Hoof, H Bhat, E Alt, B Iskaros, A Limaye, R D Luff, M McNeeley, B Winkler, A Molijn, W Quint, L Struijk, M Van de Sandt, L J Van Doorn, N Kiviat, K P Klugman, P Nieminen, C Bergeron, E Eisenstein, R Marks, T Nolan, S K Tay

Abstract

Background: The control arm of PATRICIA (PApilloma TRIal against Cancer In young Adults, NCT00122681) was used to investigate the risk of progression from cervical HPV infection to cervical intraepithelial neoplasia (CIN) or clearance of infection, and associated determinants.

Methods and findings: Women aged 15-25 years were enrolled. A 6-month persistent HPV infection (6MPI) was defined as detection of the same HPV type at two consecutive evaluations over 6 months and clearance as ≥2 type-specific HPV negative samples taken at two consecutive intervals of approximately 6 months following a positive sample. The primary endpoint was CIN grade 2 or greater (CIN2+) associated with the same HPV type as a 6MPI. Secondary endpoints were CIN1+/CIN3+ associated with the same HPV type as a 6MPI; CIN1+/CIN2+/CIN3+ associated with an infection of any duration; and clearance of infection. The analyses included 4825 women with 16,785 infections (3363 women with 6902 6MPIs). Risk of developing a CIN1+/CIN2+/CIN3+ associated with same HPV type as a 6MPI varied with HPV type and was significantly higher for oncogenic versus non-oncogenic types. Hazard ratios for development of CIN2+ were 10.44 (95% CI: 6.96-15.65), 9.65 (5.97-15.60), 5.68 (3.50-9.21), 5.38 (2.87-10.06) and 3.87 (2.38-6.30) for HPV-16, HPV-33, HPV-31, HPV-45 and HPV-18, respectively. HPV-16 or HPV-33 6MPIs had ~25-fold higher risk for progression to CIN3+. Previous or concomitant HPV infection or CIN1+ associated with a different HPV type increased risk. Of the different oncogenic HPV types, HPV-16 and HPV-31 infections were least likely to clear.

Conclusions: Cervical infections with oncogenic HPV types increased the risk of CIN2+ and CIN3+. Previous or concomitant infection or CIN1+ also increased the risk. HPV-16 and HPV-33 have by far the highest risk of progression to CIN3+, and HPV-16 and HPV-31 have the lowest chance of clearance.

Conflict of interest statement

Competing Interests: The authors have the following interests: DD, GD, LB, FS and DR are paid employees of the GlaxoSmithKline group of companies, the funder of this study. DD, DR, GD, LB and FS own stocks in GlaxoSmithKline Biologicals SA, and GD receives royalties from Wyeth Vaccines. SMG owns stock in CSL Ltd. AS, MRDRR, SMG, UJ, XC have received grants/funding through their institutions to do research for GlaxoSmithKline Biologicals SA. JP has received grants/funding through their institutions to do research for GlaxoSmithKline Biologicals SA and Merck Sharp & Dohme. FXB has received, via his institutions, educational grants from GlaxoSmithKline Biologicals SA and Merck Sharp & Dohme, Sanofi Pasteur MSD; JH has received grants through his institution by Kentucky Pediatric and Adult Res. DA has received grants through his institution by VL-Medi, Väestöliitto. CMW, JCT and SRS have received grants/have grants pending from GlaxoSmithKline Biologicals SA; JS, SMG and XC have received grants/have grants pending from GlaxoSmithKline Biologicals SA and Merck Sharp & Dohme, and XC from Sanofi Pasteur MSD. SMG and SRS have received grants/have grants pending from CSL Ltd; JS has received grants from Qiagen; CMW has received reagents and equipment through the Unviersity of New Mexico for HPV genotyping from Roche Molecular Systems. MCB, SMG and TFS have received consulting fees from GlaxoSmithKline Biologicals SA; AS, XC have received consulting fees or honoraria from GlaxoSmithKline Biologicals SA and Merck Sharp & Dohme, and XC from Sanofi Pasteur MSD; MRDRR, have received honoraria from GlaxoSmithKline Biologicals SA; FYA, JCT, SMG, SRS and TFS have received payment for board membership by GlaxoSmithKline Biologicals SA; WAJP has have received payment, via his institution for board membership, consultancy and expert testimony; AS, FYA, JCT, MJG, NSC, SMG, TFS, WAJP and XC have received payment for lectures including service on speakers bureau; AS, FYA, SMG and TFS have received payment for the development of educational presentations; AS, CMW, FYA, JCT, JH, MJG, MRDRR, SMG, SRS, UJ and XC have received travel reimbursements from GlaxoSmithKline Biologicals SA. DA has received travel reimbursements from VL-Medi. FXB and XC have received travel reimbursement from Merck Sharp & Dohme, Sanofi Pasteur MSD. NSDC has received travel reimbursement from IPAMICover DTG. J Palmroth has been invited to international gynecological cancer congresses by Merck Sharp & Dohme, Sanofi Pasteur MSD and Roche who sponsored congress fees and travel costs. BR has received payment for consultancy, payment for lectures including service on speakers bureau and support for travel via her institution by B Romanowski Prof Corporation. FXB has received support for travel and honorarium for speaking at meeting organized by GlaxoSmithKline Biologicals SA, Merck Sharp & Dohme, Sanofi Pasteur MSD. There are no patents, products in development or marketed products to declare. This does not alter our adherence to all the PLOS ONE policies on sharing data and materials, as detailed online in the guide for authors. Dr. Szarewski passed away prior to the publication of the paper. The corresponding author, Unnop Jaisamrarn, has supplied the information regarding her contributions to the manuscript and her competing interests and they are correct to the best of his knowledge.

Figures

Figure 1. Subject disposition.
Figure 1. Subject disposition.
From the 9337 women enrolled in the control arm of the PATRICIA trial, 4512 were excluded from the present analyses including 4431 subjects with no cervical HPV infection detected during the 48 months of follow-up. 4825 women representing 16785 cervical HPV infections (blue) were included and two sub-cohorts were constituted: women with a 6-month persistent HPV infection (6MPI) (n = 3363 representing 6902 infections) (light blue) and women with a natural clearance of the HPV infection (n = 4011 representing 10983 clearances) (light purple). The numbers of women and of CIN1+/CIN2+/CIN3+ lesions were calculated after exclusion of the lesions occurring after 48 months for any duration of HPV infection (blue) and for 6MPI (light blue). Among the 119 subjects with 6MPI and CIN3+, 9 had AIS (11 episodes). Among the 124 subjects with an infection of any duration and CIN3+, 10 had AIS (13 episodes). No invasive cervical cancer was found. 6MPI: 6-month persistent infection; CIN: cervical intraepithelial neoplasia; HPV: human papillomavirus; TVC-E: total vaccinated cohort for efficacy.
Figure 2. Risk of progression of a…
Figure 2. Risk of progression of a 6MPI to CIN2+ or CIN3+ associated with the same HPV type.
2a. CIN2+ 2b. CIN3+ Kaplan–Meier Estimates of Cumulative Risk (%) of Developing CIN2+ Lesions (Figure 2a) or CIN3+ Lesions (Figure 2b) Associated with the Same HPV Type Were Calculated for HPV-16, HPV-18, HPV-31, HPV-33, HPV-45, Other Oncogenic HPV Types and Non-Oncogenic HPV Types
Figure 3. Cumulative chance of clearing a…
Figure 3. Cumulative chance of clearing a cervical HPV infection (prevalent and incident infections).
3a. Duration of infection 3b. HPV type (infection of any duration) Kaplan–Meier estimates of probability of clearance (%) were calculated for transient, less than 6-month persistent HPV infection (6MPI), 6MPI and overall (Figure 3a) or according the HPV types (Figure 3b): HPV-16, HPV-18, HPV-31, HPV-33, HPV-45, other oncogenic HPV types and non-oncogenic HPV types.
Figure 4. Summary according to HPV type…
Figure 4. Summary according to HPV type of prevalence in 6MPI, risk of progression to CIN3+ lesion and chance of clearance.
Dark-shaded boxes: high prevalence (>10%), high risk of progression (HR >20) or low chance of clearance (HR

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